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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: William Cutchin, (703) 305

- 7990

TEMPLATE:

Huntsman Corporation

I N

- 10683

EPA has received a pesticide petition IN

- 10683 from Exponent, Inc., 1150 Connecticut Ave., NW, Suite 1100, Washington, DC, 20036 on behalf of Huntsman Corporation

, 8600 Gosling Road, The Woodlands, TX, 77381 request ing, pursuant to section 408(d) of the Feder al Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish an exemption from the requirement of a tolerance for di

- n

- butyl carbonate, CAS RN 542

- 52

- 9, as an inert ingredient in non

- food and food use pesticide in 40 CF R §180.910 for pre

- and post

- harvest applications; 40 CFR §180.930 for animal uses and applications; and 40 CFR §180.940 (a)(b)(c) for tolerance exemptions for active and inert ingredients for use in antimicrobial formulations (f ood

contact surface saniti zing solutions).

EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the da ta supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. Not applicable/Not required for the establishment of a tolerance exemption for inert ingredients

.
2. Analyt ical method

. Not applicable/Not required for the establishment of a tolerance exemption for inert ingredients

.
3. Magnitude of residues. There is not any spe cific crop residue information

a vailable for di

- n

- butyl carbonate. This information is typically not available or required for the establishment of a tolerance exemption for inert ingredients

. B. Toxicological Profile

1. Acute toxicity

. Potential human exposure from the use of di

- n

- butyl carbonate as pesticide inert ingredient could primarily occur via the oral route through the consumption of food or drinking water. Di

- n

- butyl carbonate was tested in six acute toxicity studies. The2

testing results indicate that the product exhibits low acute toxicity by oral, dermal and inhalation exposure routes. T he product is moderately irritating to the eyes and was negative for dermal sensitization. Di

- n

- butyl carbonate was however, irritating to the skin producing moderate to severe erythema from Days 1 to 8 with 4 hours of exposure. The irritation, however, su bsides by Day 9.

2. Genotoxicty

. Di n

- butyl carbonate was negative in a Bacterial Reverse Mutation Assay (OPPTS 870.5100/OECD guideline 471) using Salmonella typhimurium tester strains TA98, TA100, TA1535 and TA1537 and Escherichia coli tester strain WP2 uvrA in the presence and absence of Aroclor

- induced rat liver S9 [8]. At concentrations ranging from 1.5 to 5000 ug per plate, no positive mutagenic response was observed

.
3. Reproductive and developmental toxicity

. Results reported from OPPTS 870.3650 (OECD 422) Combined Repeated Dose Toxicity Study with the Reproductive and Developmental Toxicity Screening Test.

EDSA 09/12 (di

- n

- butyl carbonate) was administered daily to Wistar Hannover rats (12 animals/sex/group and 5 animals/sex/satellite groups) b y gavage, on a 7 day per week basis (from 14 days before mating period to 4 days post

- delivery). Satellite groups consisted of control (0 mg/kg bw/day) and high dose level (750 mg/kg bw/day) groups and were administered the test material for 28 days, were not mated, and were kept for 14 days after the treatment period for observation of reversibility of toxic effects. The test item was administered to animals in the main study at doses of 0 (vehicle control), 250, 500 and 750 mg/kg bw/day. The control group received the vehicle alone (deionized water). The dosage levels (in mg/body weight/day) were selected in agreement with the Sponsor, based upon the results of a dose range

- finding study (P.T. 3984.329.004.11).

Animals were checked daily for mortality or morbidity. Body weight of males

was r ecorded on the first day of dosing and weekly thereafter (including mating and post

mating periods). Females were weighed on first day of dosing and once a week thereafter; during the premating and mating periods, on d ays 0, 7, 14 and 20 of gestation and during lactation on the same days as the weighing of the litters (on day 0 and 4 postnatal). Food consumption was determined on the same day of body weight determination during premating and lactation periods. During th e gestation period, food consumption was determined on days 3, 6, 9, 12, 15, 18 and 20. After the mating period, food consumption of males was determined weekly. Animals were subjected to a careful clinical examination prior to the initiation of the treatm ent and once a week thereafter

. Functional observation battery (FOB) was performed in 5/animals/sex/group on males at the end of the dosing period and for females during lactation (day 3). At the end of the
treatment period, the animals were submitted for overnight fasting. On the day of necropsy, the animals were weighed and anesthetized by CO 2 inhalation. Blood samples were collected by c ardiac puncture (from 5/animals/sex/group) for hemogram and clotting analyses, leukogram and clinical chemistry. During necropsy, the animals were subjected to a complete gross examination of organs and tissues. The total number of implantation sites and corpora lutea was counted. The appropriate organs and tissues (from 5/animals/sex/group) were removed, weighed and submi tted for histopathological fixation. Full histopathology of the preserved organs and tissues was performed in the3

high dose and control animals and in selected tissues of other animals in other dose groups, which presented findings in macroscopic observati ons.

The di

- n

- butyl carbonate test material (EDSA 09/12) did not result in any test material

- related mortality or clinical observations in the study. No effects were observed in the functional observational battery, hematology and clotting parameters, cli nical chemistry parameters or organ weights. No macroscopic findings related to the test item were observed. No histopathological effects were reported in neurological tissues (cerebrum, cerebellum, pons, peripheral nerve, spinal cord) (cervical, midthorac ic and lumbar sections) or any immunological tissues (bone marrow, thymus, spleen, lymph nodes).

Although the study authors stated that no effects on body weight, body weight gain or food consumption were observed or considered to be treatment

- related, la rge, albeit not uniformly statistically significant body weight gain deficits were sporadically observed. Differences in body weights and body weight gains were observed in treated males and females compared to the control group. In the main study, female body weight gain premating from day 0

- 7 was reduced by 26.6% in the 750 mg/kg bw/day dose level (no statistical significance) and was reduced by 56.2% in the 500 mg/kg bw/day dose group (no statistical significance) when compared to the control group. Thes e deficits in body weight gain premating from day 0

- 7 did not show any dose

- response relationship. A similar not statistically significant decrease in body weight gain from days 0

- 7 in the satellite females occurred at 750 mg/kg bw/day (11.9%) when compare d to controls. Body weight gain during gestation days 14

- 20 was statistically significantly reduced in the 750 mg/kg bw/day treatment group by 38.5% when compared to the control group and overall gestation body weight gain (gestation days 0

- 20) was reduced by 21.3% (not statistically significant) when compared to control. Body weight gain during lactation (Days 0

- 4) was also reduced (not statistically significant) by 71.5% in the high dose females. In the satellite group females, body weight gain was non

- si gnificantly reduced from Days 14

- 21 by 59.5% when compared to the control. Food consumption in the main study females in the 750 mg/kg bw/day group was slightly reduced throughout the study (premating through gestation) without statistical significance whe n compared to the control group females. The exception was for lactation (Days 0

- 4) where the food consumption was statistically significantly reduced (22.5%), corresponding with the decreased body weight gain in this group. In the satellite study females, the food consumption in the 750 mg/kg bw/day group was generally less than controls throughout the study period for females without statistical significance. A similar non

- statistically significant reduction in body weight gain was observed in the males. Overall body weight gain in the males during the entire treatment period was reduced by 11.2% in the main study and 37.3% in the satellite animals compared to res pect ive controls. The largest difference was during study days 0

- 7 (

- 32.7% for the main study) , stud y days 7

- 14 (

- 22.7% and

- 143% (statistically significant)), for the main study and satellite st udy

, respectively) and study days 14

- 21 (

- 88.2% for the satellite study). Food consumpti on

was slightly reduced in the satellite group males and was gener ally comparable to

con trols in the main group (males).4

The study authors stated in the final report that high dose dams showed higher
pr e

- and postimplantation losses, lower fertility and lower gestation index when compared to the control animals. Th ese findings were considered test item related with slight toxicological relevance.

BioAgri historical control data were not included in the final report; control data from a recent n

- butyl benzoate OPPTS 870.3650 (OECD 422) study is available (Martell 201 3b) and was used to analyze the data for this study (Martell 2013a). This study was submitted to EPA by Huntsman in support of a separate tolerance exemption petition (MRID not yet assigned). Further analysis of the fertility index did not indicate a decre ase in the index based on data from a recent study (Martell, 2013b). The current study reports 11 pregnant out of 12 mated animals (92.3%) in the control, 250 and 500 mg/kg bw/day and 10/12 mated animals (83.3%) for the 750 mg/kg bw/day groups. However, in the recent n

- butyl benzoate study, the control group fertility index was 75%. (Martell 2013b). Therefore, the fertility index finding in the di

- n

- butyl carbonate study is not attributable to the test material. Similar evaluation of the gestation index dat a was performed. In the same recent study by Martell (2013b), the gestation index of the control animals was reported as 77.7% for n

- butyl benzoate. Therefore, the gestation index finding of 80% for di

- n

- butyl carbonate was within controls reported for Bio Agri and therefore is not attributable to the test material. In Martell (2013b), the pre

- implantation loss for the control group in the butyl benzoate study was 44.3%, which is higher than the 42.2% reported in the high dose group for this study. In additi on to pre

- implantation and post

- implantation losses in this study (Martell 2013a), total pups (pups born live) were statistically lower at 750 mg/kg bw/day (5.7) when compared to the control group (11.7). No alterations on pup body weights were observed be tween control and treated groups between days 0 to 4 postnatal and no macroscopic findings were observed in treated or control groups.

Although the study authors reported that the No Observed Adverse Effect Level (NOAEL) was 750 mg/kg bw/day for parental a nd embryo

- fetal toxicity, assessment of the data reported in the study reveal that the NOAEL of the test item n

- di

- butyl carbonate (EC 09/12) in Wistar Hannover rats may be 500 mg/kg bw/day for parental animals (males and females) and 500 mg/kg bw/day base d upon embryo

- fetal toxicity.

The Lowest Observed Adverse Effect Level (LOAEL) should be considered to be 750 mg/kg bw/day based on decreased body weight gain in male and female paternal animals and embryo

- fetal toxicity at 750 mg/kg bw/day as evidenced by increased pre

and post

- implantation losses and decreased total number of pups (Martell 2013a).]

4. Subchronic toxicity. The general systemic NOAEL from the 28

- Day OPPTS 3650.2000 (OECD 422) Combined Repeated Dose Toxicity Study with a Reproduction /Developmental Toxicity Screening Test in rats is 500 mg/kg body weight/day.

5. Chronic toxicity. No chronic toxicity data for di

- n

- butyl carbonate are available. B ased on the Federal Register Notice (August 9, 2006, Volume 71, Number 153, pages 45415

- 45424), the Agency stated that the preferred test for repeat

- dose toxicity is the "Combi ned R epeated Dose Toxicity Study with the5

Reproduction/D evelopmental Toxicity Screening Te s t ( OECD T e st Guideline 422)." Therefore, an OPPTS 3650.2000 (OECD 422) study has been s u bm i tted and t h e results are summarized under the Reproductive and Deve lopmental Toxicity, Sec tion 3, of this document.

6. Animal metabolism. Esterase mediated hydrolysis is a well

- established primary pathway by which all esters are metabolically degraded. If ingested di

- n

- butyl carbonate would be readily hydrolyzed by esterases in the gut to gen erate two molar equivalents of

n

- butyl alcohol and one molar equivalent of carbonic acid (aqueous CO 2 solution). The n

butanol log Kow = 0.88 and as such, is considerably less than the parent carbonate ester, which has a log Kow = 3.18. Thus, the n

- butanol metabolite would be rapidly excreted and/or be oxidized sequentially by alcohol dehydrogenase and aldehyde dehydrogenase to generate butanoic acid, which is degraded through p

- oxidation to generate CO 2 and H 2 O

7. Metabolite toxicology

. No metabolites of toxicological concern are expect ed based on the reported animal metabolic pathway for ester hydrolysis to generate n

- butyl alcohol and carbonic acid ( CO 2 ) as the primary metabolites.

8. Endocrine disruption

. Di

- n

- butyl carbonate does not belong to a class of chemicals designated or potentially design ated as endocrine disrupters. Although at some future date EPA may screen di

- n

- butyl carbonate for potential estrogen, androgen and thyroid ( EAT ) hormonal effects in the Endocrine Disruptor Screening Program ( EDSP ) assays, the current repeat dose database of mammalian toxicology studies, that includes reproductive and developme ntal toxicity testing, does not indicate potential adverse EAT hormonal effect

.

C. Aggregate Exposure

In examining aggregate exposure, FFDCA section 408 directs EPA to consider available information c oncerning exposures from the pesticide residue in food and all other nonoccupational exposures, including drinking water from ground water or surface water and exposure through pesticide use in gardens, lawns, or buildings (residential and other indoor use s). It is unlikely that humans (adults and children) would be exposed to d i

- n

- b utyl c arbonate via potential residues on foods and in drinking water.

1. Dietary exposure

. The dietary (food plus drinking water) exposures for di n

butyl carbonate are expressed as a percentage of the proposed chronic population adjusted dose (cPAD) for the general US population and children 1

- 2 years old, the subpopulation with the highest potential exposures.
Although the NOAEL for di

- n

- butyl carbonate in OPPTS 870.3650.2000 (OECD 422) study is reported as 750 mg/kg bw/day for parental and embryo

- fetal toxicity, assessment of the data reported in the study reveal that the NOAEL of the test item n

- di

butyl carbonate (EC 09/12) in Wistar Hannover rats may be 500 mg/kg bw/day for parental animals (males and females) and 500 mg/kg bw/day for embryo

- fetal toxicity.6

The Level (LOAEL) should be considered to b 750 mg/kg bw/day based on decreased body weight gain in male and female paternal animals an d embryo

- fetal toxicity at 750 mg/kg bw/day as evidenced by increased pre

- and post

- impla n tat i on losses and decreased total number of pups. Th e chronic reference dose (cRfD) is there f o re

co nservati vely proposed to be 5 mg/kg/day ( 500 mg/kg bw/day ÷ 1 00 )

. The available data for the proposed non

- food and food use patterns of use support that the FQPA safety factor for di

- n

- butyl carbonate should be reduced from 10X to IX (Section E. Safety Determination). Therefore, only the 10X factors for intra

- and inter

species variability should be included in calculating the chronic population adjusted dose (cPAD = cRfD ).

EPA assesses potential dietary exposures to inert ingredients used in agricultural pesticide formulations using a screening

- level model referred to as "I

- DEEM," in which the "I" stands for inerts and "DEEM" is the dietary exposure evaluation model that is used by EPA to assess dietary exposures to active ingredients in pesticide products. EPA's Inert Ingredient s Assessment Branch and residue chemists in the Health Effects Division of the Office of Pesticide Programs jointly developed I

- DEEM. The model, as devel oped by EPA, uses crop

- specific residue data (i.e., maximum tolerances) for 57 active ingredients as surrogates for potential inert ingredient residue levels. I

- DEEM estimates that inert ingredients are used on all crops, and that 100 percent of all crops are assumed to be "treated" with the inert ingredient(s). I

- DEEM will assume that the inert is present at a concentration of 50% in all the pesticide formulations. In addition, EPA includes potential residues of 100 ppb in water for potential drinking water exposures. Using these assumptions, and including no cap for use as an inert ingredient in the food use pesticide formulations supported by way of t h is petition, the chronic dietary exposure is estimated to be 0.189 mg/kg/day for the general U.S. population

, 0.706 mg/kg/day for children 1

- 2 years of age (i.e., the most highly exposed subpopulation).

Thus, based on I

- DEEM screening level calculations, the chronic dietary exposures are estimated to be 3.78% of the cPAD for the general U.S. population and 14.12% of the cPAD for children 1

- 2 years old.

These data demonstrate that the I

- DEEM screening

- level chronic dietary (food and drinking water) exposures are below the cPAD and are therefore below EPA's establish ed level of concern for all U.S. subpopulations.

i. Food

. The available data demonstrate that the I

- DEEM screening level chronic dietary (food and drinking water) exposures are well below 100% of the cPAD, and are therefore below EPA's established level of concern for all U.S. subpopulations.

ii. Drinking water

. Drinking water is included in the I

- DEEM exposure
assessment

. Exposure to di n

- butyl carbonate via drinking water is expected to be negligible

.7

2. Non

- dietary exposure

. Given the low estimate of dietary exposure, t here is ample room in the overall aggr egate margin of exposure ( MOE ) for non

- dietary uses.

D. Cumulative Effects

Section 408(b)(2)(D) (9v) of the FFDCA requires that, when considering whether
to establish, modify, or revoke a tolerance, the Agency considers "available information" concerning the cumulative effects of a particular p esticide's residues and "other substances that have a common mechanism of toxicity." Unlike pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not conducted a common mechanism evaluation for di

- n

- butyl carbonate. Moreover, di

- n

- butyl carbonate does not produce a toxic metabolite(s) that may have a common mechanism of toxicity with other substances.

For information regarding EPA's efforts to determine which chemicals have a common mechanism of to xicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a commo n mechanism (http://www.epa.gov/pesticides/cumulative/.

E. Safety Determination

1. U.S. population. A dietary exposure assessment using current EPA inert screening level methodology (I

- DEEM) was conducted. Based on the conservative I

DEEM dietary exposure estimates, there is a reasonable certainty that no harm will result to the U

. S

. population from the aggregate exposure to di

- n

- butyl carbonate.

2. Infants and children

. The FFDCA Section 408 requires an additional tenfold margin of safety for the protection of infants and children in case of threshold effects to account for prenatal and postnatal toxicity, and an inadequate toxicity database. Where an adequate and reliable database is available and there is a lack of evidence for increased susceptibility, the FQPA safety fa ctor may be reduced or removed.

Based on available information discussed thus far and below in Special Consideration for Infants and Children, Huntsman requests reduction of the FQPA safety factor to IX and that the additional tenfold safety factor for the protection of infants and children be removed.

Completeness of the Toxicological Database A scientifically sound and robust mammalian toxicology database that includes acute toxicity, subchronic toxicity, reproductive toxicity, developmental toxicity and genotoxicity data is available and is adequate for characterizing the toxicity of di

- n

- butyl carbonate and for the quantification of hazard for dietary exposure assessment. No immunotoxicological or neurotoxicity findings were reported in the8

database. The re are no residual uncertainties for pr e

- and/or post

- nata l toxicity

.

Di

- n

- butyl carbonate does not belong to a class of chemicals tha t is known

or suspected to affect the estrogen receptor or have any adverse effects, o n the endocrine system.

Evidence of Neurotoxicity There is no evidence of neurotoxicity in the toxicological database for di

n

- butyl carbonate. In the OPPTS 870.3650 (O ECD 422) Combined Repeated Dose Toxicity Study with the Reproductive and De velopmental Toxicity Screening Test, no clinical effects indicative of neurotoxicity were reported, no adverse findings were reported from the functional observational battery (FOB) assessments conducted in the study, and no

neuro

- pathological findings were reported in the study.

Evidence of Sensitivity/Susceptibility in the Developing or Young Animal Offspring effects at the high dose levels of 750 mg/kg bw/day were associated with ma ternal toxicity in the form of statistically significant body weight gain during gestation. Significant offspring effects at 750 mg/kg bw/day were limited to increased pre

- and post

- implantation mortality with decreased number of pups on Day 0. All effects to the pups and parental generation animals were reported only at the high dose level and a clear NOAEL (500 mg/kg bw/day) was identified for all effects.

Considering the overall toxicity profile and the endpoints and doses selected for di

- n

- butyl carbonat e, the degree of concern for the effects observed in the di

- nbutyl carbonate reproductive and developmental toxicity screening study is low; noting that there is a clear NOAEL for the offspring effects and regulatory doses were selected to be protective of these effects. No other residual uncertainties were identified with respect to susceptibility. The endpoints and doses selected for the dietary risk assessment of di

- n

- butyl carbonate are protective of adverse effects in both offspring and adults.

In conj unction with the n

- butanol tolerance reassessment, EPA (2005) has
not expressed concern that n

- butanol, the major metabolite for di

- n

- butyl carbonate, may cause adverse effects in sensitive populations, infants and children.

"Thus based on the available in format ion there is no concern at this time for increased sensitivity to infants and children to n

- butanol and isobutyl alcohol when used as an inert ingredient in pesticide formulations. For the same reason, a safety factor analysis has not been used to as sess risk and, therefore, the additional tenfold safety9

factor for the protection of infants and children is also unnecessary."

Residual Uncertainty in the Exposure Database The dietary risk assessment for di

- n

- butyl carbonate is based on conservativ e high

- end assumptions (over

- estimates) of dietary exposures. Estimated diet a ry exposure is based on assumed resid ues from the foliar application of pesticide s products in which the inert ingredient is assumed to be present in a con centration of 50%. As such, the exposure assessment is likely to overesti mate actual e xposures. With the standard application of intra

- and inter

- specie s v ariabilit y , uncertainty factors, the clear NOAEL, 500 mg/kg/bw/day, for th e offs pring effect from the OPPTS 870 .3650 (OECD 422) Combined Repeated D ose Tox icity Study with the Reproductive and Developmental Toxicity Screening Test by is protective of potential effects to potentially exposed human population s. No other residual uncertainties were identified wi th respect to susceptibility. The endpoints and doses selected for di

- n

- butyl carbonate are protective of adverse effects in both offspring and adults.

The physicochemical/environmental properties indicate that significant crop residues and resultant dieta ry exposures to sensitive populations are unlikely.

Additionally, I

- DEEM modeling supported that the estimated dietary exposures to di

- n

- butyl carbonate for children 1

- 2 years of age, the potentially most exposed population, is 14.2%, and therefore, below the 100% of the cPAD.

F. International Tolerances

There are no known i nternational tolerances for di

- n

- butyl carbonate

.